High purity 2-[4-(3- or 2-fluorobenzyloxy)benzylamino] propanamides and methods of use thereof
Inventors
Barbanti, Elena • Faravelli, Laura • Salvati, Patricia • Canevotti, Renato • Ponzini, Francesco
Assignees
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Publication Number
US-8846763-B2
Publication Date
2014-09-30
Expiration Date
Abstract
A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides, and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight. The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to a reduction reaction with a reducing agent selected from sodium borohydride and potassium borohydride in an appropriate amount of an organic solvent selected from C1-C5 lower alkanols, allowing the formation and presence during a substantial position of the reduction reaction course of a suspension of the Schiff base into the saturated solution of the Schiff base into the same organic solvent.
Core Innovation
The described process produces high-purity safinamide (Ia) and ralfinamide (Ib) and related R-enantiomers and racemates, including methanesulfonate salts. The process converts fluorobenzyloxy benzaldehydes to Schiff base intermediates and then reduces the Schiff base intermediates using sodium borohydride and/or potassium borohydride in lower alkanol solvents (C1-C5) under conditions that maintain a Schiff-base suspension in a saturated solution to obtain high HPLC purity products and the corresponding methanesulfonate salts.
A key aspect is stringent control of specific dibenzyl derivative impurities (IIa/IIb and corresponding R-impurities II′a/II′b) and their salts, particularly methanesulfonates. The text states that prior large-scale methods produce impurity levels above 0.03% and sometimes about 0.3%, and the process is therefore directed to impurity limits of less than 0.03% by weight and preferably less than 0.01% by weight.
The background discusses prior art involving one-pot iminoalkylation and reduction steps using cyanoborohydride or borohydride, molecular sieves, and large solvent volumes, and it explains drawbacks including elevated dibenzyl derivative impurities. The described approach combines conversion to Schiff base intermediates from fluorobenzyloxy benzaldehydes with hydride reduction in lower alkanols while maintaining a Schiff-base suspension in saturated solution, together with salt formation using methanesulfonic acid.
Claims Coverage
Not explicitly described in patent.
Not explicitly described in patent.
Stated Advantages
Reduces specific dibenzyl derivative impurities, including R-impurities, to less than 0.03% by weight, preferably less than 0.01% by weight.
Improves safety by avoiding impurity levels described as highly toxic and inhibitory toward CYP450 isoforms and HERG.
Helps preserve in vivo efficacy by avoiding impairment described for higher impurity levels.
Provides high HPLC purity safinamide and ralfinamide products and corresponding methanesulfonate salts.
Documented Applications
CNS treatment using safinamide with impurity control as described in safinamide-related uses.
Treatment of disease states associated with sodium/calcium channel effects using ralfinamide with impurity control as described in ralfinamide-related uses.
R-enantiomer treatment using safinamide R-enantiomers with impurity threshold control.
R-enantiomer treatment using ralfinamide R-enantiomers with impurity threshold control.
Pain treatment using safinamide with impurity threshold control.
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